About 28.3 million Americans have type II diabetes (T2D) and over 40.1% of middle-aged adults have prediabetes, a condition characterized by impaired glucose tolerance and insulin resistance. Current antidiabetic medications are effective in improving insulin sensitivity, but their chronic administration has significant side effects suc as cardiovascular complications, hepatotoxicity, adipose tissue accumulation, and fluid retention, bladder tumors. We have discovered a naturally occurring isoprenoid, abscisic acid (ABA) that increases insulin sensitivity and suppresses inflammation in overweight and obesity. Recently, we have identified Lanthionine Synthetase Component C-Like 2 (LANCL2) as a novel molecular target for ABA. This project will evaluate the efficacy and safety of novel ABA derivatives for treating diabetes. The specific aims for the proposed STTR Phase I are: (1) To generate 20 derivatives and analogs of ABA for development of diabetes and obesity-related inflammation drugs; (2) To perform in silico and in vitro screening to select lead derivatives for further development; and (3) To compare the oral efficacy of ABA-derived drugs against pioglitazone, an approved diabetes drug, in two mouse models of diabetes. At the conclusion of this effort our team will have identified two derivatives of ABA that have undergone extensive in vitro testing and are safe and with proven efficacy in two mouse models of diabetes. We will have filed at least one patent application with robust composition of matter claims for the new class of anti-diabetic drugs that target the LANCL2 pathway. The proposed studies will differentiate the mode of action (MOA) of ABA and its new derivatives from binding to peroxisome proliferator-activated receptor g. This work will provide an excellent assessment of the feasibility of developing novel ABA-based treatments for diabetes. STTR Phase II will optimize two of the lead compounds with demonstrated efficacy in mouse models of diabetes and advance them along the regulatory pathway, including efficacy, mode of action, absorption, distribution, metabolism and excretion, phamacokinetics/pharmacodynamics, toxicokinetics analysis and toxicity assessment working towards the testing required to submit an investigational new drug application in preparation for human clinical trials. To optimize oral drug delivery we shall develop more analogs that have molecular properties (ClogP, molecular weight, polar surface area, numbers of rings, rotable bonds, N and O atoms, hydrogen bond donors and acceptors) within the guidelines; and test their efficacy and safety. Long Term Goal: The goal of BioTherapeutics (BTI) technology will be to provide an oral therapeutic alternative to existing diabetes treatments that costs less and provides greater efficacy with reduced adverse side effects. The technology will address the overlying health problem with patients suffering with diabetes and will provide a significant commercialization potential to a market of 28.3 million estimated to be over $12.5 Billion for prescription medication costs alone annually in the US.